Morphological characterization of the ovary under normal cycling in rats and its viewpoints of ovarian toxicity detection

Yoshida, Midori; Sanbuissyo, Atsushi; Hisada, Shigeru; Takahashi, Michihito; Ohno, Yasuo; Nishikawa, Akiyoshi

doi:10.2131/jts.34.s189

Cited by 49 publications

(34 citation statements)

References 19 publications

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“…Sections were stained with hematoxylin and eosin. For morphological analysis, a representative section of the largest cross-sectional area of 1 ovary and 1 uterine horn was blindly selected for each rat (39). Quantitative analysis was conducted using an image-combining computer microscope (Nikon) equipped with a motorized stage (Ludl Electronics Products), a Lucivid miniature cathode ray tube, and NeuroLucida software (MicroBrightField).…”

Section: Experiments 1 Effects Of Kndy Neuron Ablation On Gonadotropimentioning

confidence: 99%

Ablation of KNDy Neurons Results in Hypogonadotropic Hypogonadism and Amplifies the Steroid-Induced LH Surge in Female Rats

et al. 2016

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In the human infundibular (arcuate) nucleus, a subpopulation of neurons coexpress kisspeptin and neurokinin B (NKB), 2 peptides required for normal reproductive function. A homologous group of neurons exists in the arcuate nucleus of rodents, termed KNDy neurons based on the coexpression of kisspeptin, NKB, and dynorphin. To study their function, we recently developed a method to selectively ablate KNDy neurons using NK3-SAP, a neurokinin 3 receptor agonist conjugated to saporin (SAP). Here, we ablated KNDy neurons in female rats to determine whether these neurons are required for estrous cyclicity and the steroid induced LH surge. NK3-SAP or Blank-SAP (control) was microinjected into the arcuate nucleus using stereotaxic surgery. After monitoring vaginal smears for 3-4 weeks, rats were ovariectomized and given 17β-estradiol and progesterone in a regimen that induced an afternoon LH surge. Rats were killed at the time of peak LH levels, and brains were harvested for NKB and dual labeled GnRH/Fos immunohistochemistry. In ovary-intact rats, ablation of KNDy neurons resulted in hypogonadotropic hypogonadism, characterized by low levels of serum LH, constant diestrus, ovarian atrophy with increased follicular atresia, and uterine atrophy. Surprisingly, the 17β-estradiol and progesterone-induced LH surge was 3 times higher in KNDy-ablated rats. Despite the marked increase in the magnitude of the LH surge, the number of GnRH or anterior ventral periventricular nucleus neurons expressing Fos was not significantly different between groups. Our studies show that KNDy neurons are essential for tonic levels of serum LH and estrous cyclicity and may play a role in limiting the magnitude of the LH surge.

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Section: Experiments 1 Effects Of Kndy Neuron Ablation On Gonadotropimentioning

confidence: 99%

Ablation of KNDy Neurons Results in Hypogonadotropic Hypogonadism and Amplifies the Steroid-Induced LH Surge in Female Rats

et al. 2016

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“…However, as luteal morphology differs from stage to stage within 1 estrus cycle, additional studies are needed to characterize luteal morphology characteristics at each stage of the estrus cycle in the rat. Yoshida et al (2009) provided a practical guide to ovarian morphology in rats with normal cycling. They classified CL into 2 types, currently formed CL and previously formed CL, and characterized them at each stage of the estrus cycle.…”

Section: Discussionmentioning

confidence: 99%

Histopathological Characteristics of Luteal Hypertrophy Induced by Ethylene Glycol Monomethyl Ether with a Comparison to Normal Luteal Morphology in Rats

Taketa¹,

Inomata²,

Hosokawa³

et al. 2010

Toxicol Pathol

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Ethylene glycol monomethyl ether (EGME) is a known reproductive toxicant that induces luteal hypertrophy in rat ovaries. In this study, we characterized the histopathological features of corpora lutea (CL) from EGME-treated rats and compared them with normal CL formation and regression. Normally cycling female Sprague-Dawley rats were treated with 5-bromo-2 0 -deoxyuridine (BrdU) intraperitoneally on the morning of estrus and their ovaries were examined 1 (metestrus), 4 (estrus), 8 (estrus), or 12 (estrus) days later to observe the transition of BrdU-labeled cells within in the CL. CL at each time point of estrus stage were classified into 4 types: Type I (newly formed CL), Type II (mature CL), Type III (regressing CL), and Type IV (residual CL). CL almost fully regressed within 4 estrus cycles. In contrast, in female rats given EGME orally (30, 100, or 300 mg/kg for 2 or 4 weeks), luteal cells were hypertrophic with abundant cytoplasm. Although the size of CL varied, all CL in EGME-treated rats had histological features similar to Type II CL, but they were more hypertrophic with less apoptosis. These results suggest that EGME has a luteal hypertrophic effect on all CL phases, including regression.

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“…The characteristics of the follicles and corpora lutea at each estrous cycle stage referred to Yoshida et al (2009). The terminology and histopathological changes observed in the validation studies were standardized by toxicological pathologists participating in several face-to-face meetings held by JMPA and NIHS.…”

Section: Methodsmentioning

confidence: 99%

Collaborative work on evaluation of ovarian toxicity by repeated-dose and fertility studies in female rats

Sanbuissho

Yoshida²,

Hisada

et al. 2009

J. Toxicol. Sci.

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-The National Institute of Health Sciences (NIHS) and 18 pharmaceutical companies of the Japan Pharmaceutical Manufacturers Association (JPMA) have conducted a validation study intended to evaluate whether a 2-week repeated general toxicity period with histopathological examination is -ing that it is adequate. Evaluation of ovarian toxicity by comprehensive histopathological examination of the female reproductive organs based on the underlying morphology of a normal cycle of the reproductive tract including the ovary and additional immunohistochemical staining with proliferative cell nuclear antigen (PCNA) to identify small follicles may be a good tool to assess female reproductive function. In the collaborative study, 2-or 4-week repeated dose toxicity studies with ovarian histopathological examinations were conducted. A female fertility study was also conducted to compare the results with those of hormone analogues, primordial follicle damaging agents, metabolite imbalance inducers, and endocrine imbalance inducers. Based on the results, ovarian toxicity could be detected by a careful histopatholgi--female fertility parameters (irregular estrous cycle, pre-implantation loss).

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Morphological characterization of the ovary under normal cycling in rats and its viewpoints of ovarian toxicity detection

Cited by 49 publications

References 19 publications

Ablation of KNDy Neurons Results in Hypogonadotropic Hypogonadism and Amplifies the Steroid-Induced LH Surge in Female Rats

Ablation of KNDy Neurons Results in Hypogonadotropic Hypogonadism and Amplifies the Steroid-Induced LH Surge in Female Rats

Histopathological Characteristics of Luteal Hypertrophy Induced by Ethylene Glycol Monomethyl Ether with a Comparison to Normal Luteal Morphology in Rats

Collaborative work on evaluation of ovarian toxicity by repeated-dose and fertility studies in female rats

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